Surgery for childhood epilepsy Sita Jayalakshmi, Manas Panigrahi1, Subrat Kumar Nanda, Rammohan Vadapalli2 Departments of Neurology and 1Neurosurgery, Krishna Institute of Medical Sciences, Secunderabad, 2Vijaya Diagnostic Centre, Hyderabad, Andhra Pradesh, India Abstract Approximately 60% of all patients with epilepsy suffer from focal epilepsy syndromes. In about 15% of these patients, the seizures are not adequately controlled with antiepileptic drugs; such patients are potential candidates for surgical treatment and the major proportion is in the pediatric group (18 years old or less). Epilepsy surgery in children who have been carefully chosen can result in either seizure freedom or a marked (>90%) reduction in seizures in approximately two-thirds of children with intractable seizures. Advances in structural and functional neuroimaging, neurosurgery, and neuroanaesthesia have improved the outcomes of surgery for children with intractable epilepsy. Early surgery improves the quality of life and cognitive and developmental outcome and allows the child to lead a normal life. Surgically remediable epilepsies should be identified early and include temporal lobe epilepsy with hippocampal sclerosis, lesional temporal and extratemporal epilepsy, hemispherical epilepsy, and gelastic epilepsy with hypothalamic hamartoma. These syndromes have both acquired and congenital etiologies and can be treated by resective or disconnective surgery. Palliative procedures are performed in children with diffuse and multifocal epilepsies who are not candidates for resective surgery. The palliative procedures include corpus callosotomy and vagal nerve stimulation while deep brain stimulation in epilepsy is still under evaluation. For children with “surgically remediable epilepsy,” surgery should be offered as a procedure of choice rather than as a treatment of last resort.
Key Words Children, epilepsy surgery, temporal lobe epilepsy, extratemporal epilepsy, hemispherotomy For correspondence: Dr. Sita Jayalakshmi, Department of Neurology, Krishna Institute of Medical Sciences,
1-8-31/1, Minister Road, Secunderabad, Andhra Pradesh, India. E-mail: [email protected] Ann Indian Acad Neurol 2014:17 (Supplement 1):S69-79
Introduction Approximately 60% of all patients with epilepsy suffer from focal epilepsy syndromes. In about 15% of these patients, the seizures are not adequately controlled with anticonvulsive drugs, and such patients are potential candidates for surgical treatment. Around 65% of newly diagnosed epilepsy patients have a good response to antiepileptic drugs (AEDs). However, about 35% of patients have incompletely controlled epilepsy.[1] A major proportion of epileptic patients falls in the pediatric group (18 years or less), and approximately 25% of them have medically intractable epilepsy. Advances in neuroimaging and neurosurgical techniques have helped in selecting an increasing number of children with refractory epilepsies into the pediatric epilepsy surgery programs. Surgery has become an accepted treatment modality for carefully selected adults with intractable focal epilepsy. Epilepsy surgery in children who have been carefully chosen Access this article online Quick Response Code:
Website: www.annalsofian.org
DOI: 10.4103/0972-2327.128665
can result in either seizure freedom or a marked (>90%) reduction in seizures in approximately two-thirds of the children with intractable seizures.[2,3] Infants and children benefit from epilepsy surgery, with encouraging results published in recent series.[4-8] Consequences of ongoing seizures in childhood Poor developmental outcome in children is associated with earlier seizure onset.[9] Ongoing seizures in severe epilepsy has been shown to be associated with developmental delay and cognitive decline, and improvement in developmental outcome may be noted with early cessation of seizures.[10] Chronic AED therapy may be associated with adverse effects. Recurrent seizures are associated with behavioral and psychiatric problems, psychosocial consequences, poor quality of life of the child and family, and increased risk of injury and sudden death.[11] Unique features of pediatric epilepsy surgery Children are not small adults. Epilepsy surgery in children requires a careful approach during presurgical evaluation and surgical approach, as it is different from adults.[4,12] 1. Seizure frequency is high in children when compared to adults. 2. Frequent seizures in infants and children is associated with developmental arrest or regression, especially in children younger than 2 years. 3. Focal epilepsy in childhood is often associated with age-specific etiologies. Dysplasia is the commonest substrate in children, whereas hippocampal sclerosis is common in adults. 4. The presentation of intractable
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localization-related epilepsy is often heterogeneous in childhood. Pediatric patients with hemispheric or unilateral focal etiologies can have generalized seizures, generalized and multifocal electroencephalography (EEG) patterns, and rapid evolution of electroclinical features. 5. The child’s brain is capable of significant reorganization of neurologic function after insult and surgery, a unique and complex phenomenon that is critical for surgical planning. For example, interhemispheric language transfer occurs in children operated below the age of 6 years. Selection of the ideal candidate Epilepsy surgery is considered in children when 1. epilepsy is refractory, which is defined as inadequate control of seizures despite proper drug therapy with AED or the adequate control of epileptic seizures but with unacceptable side effects.[12] In adults, medical intractability may be considered as failure to respond to at least two anticonvulsant drugs over at least 2 years. These rules may not be appropriate in children and infants with catastrophic-onset epilepsies as seizure frequency may be such that a greater number of drugs are tried over a shorter time. In such cases, there is a need for early surgery for seizure freedom and prevention of developmental delay. 2. To be suitable for temporal or extratemporal epilepsy surgery, it should be proven that the seizures arise exclusively from one area of the brain that is functionally silent. Such an area of the brain may be relatively small or large, dependent partly on the underlying pathology and partly on the area of brain involved. The goals of epilepsy surgery should be clear [Table 1], and one should also understand when not to consider epilepsy surgery [Table 2]. Types of epilepsy surgery Currently, four types of surgical procedures are in practice[13] [Table 3]. They include the following: 1. Resection of the epileptogenic region responsible for the patient’s habitual seizures. 2. Interruption of pathways propagating seizures. 3. Decreasing brain excitability by stimulating structures exerting a restraining influence. 4. Prevention of neuronal synchronization. Presurgical evaluation The goals of presurgical evaluation are 1. To establish the diagnosis of epileptic seizure. 2. Define the electroclinical syndrome. 3. Delineate the lesion(s) responsible for the seizures. 4. Evaluate the past AED treatments and ensure that an adequate medical treatment had been provided. 5. Select ideal surgical candidates with optimal electro-clinicoradiologic correlation. 6. Ensure that the surgery will not result in disabling neuropsychological deficits.[14] Different diagnostic tools area being used by epileptologists to identify different cortical zones — symptomatogenic zone, irritative and ictal-onset zones, epileptogenic zone, and functional deficit zone, each one of which is more or less a precise index of the epileptogenic zone.[15] The current diagnostic techniques used in the definition of these cortical zones are video EEG monitoring, magnetic resonance imaging (MRI), ictal single-photon emission computerized tomography (SPECT), and positron emission tomography (PET). A detailed developmental, neuropsychological assessment and evaluation for behavioral problems should be performed. Intracarotid amobarbital (WADA) test and functional MRI (fMRI) are indicated in
Table 1: Goals of epilepsy surgery Removal of the lesional brain tissue — epileptogenic zone. Rendering the patient free of disabling seizures. Prevention of progressive side effects of epilepsy — physical, cognitive, psychosocial. Improvement in quality of life of the child, family.
Table 2: When not to consider epilepsy surgery Multiple epileptogenic foci. Single or predominant epileptogenic zone in nonresectable area (e.g., eloquent area). Progressive and/or diffuse neurological disorder or general medical contraindication. Severe/chronic psychiatric disorder.
Table 3: Surgical techniques Resective surgery: Removal of epileptogenic region responsible for patient’s habitual seizures Anterior temporal lobectomy with amygdalohippocampectomy Selective amygdalohippocampectomy Lesionectomy Cortical dysplasia Tumors (low-grade gliomas, dysembryoplastic neuroepithelial tumors) Gliosis ( secondary to old stroke or traumatic brain injury) Cavernoma Focal cerebral calcification Hemispherectomy/hemispherotomy Disconnection surgery: Interruption of pathways propagating discharges Corpus callosotomy — to stop the interhemispheric spread and synchronization of a seizure Disconnective technique — for hypothalamic hamartoma Stereotactic ablation Brain stimulation: Vagal nerve stimulation Deep brain stimulation Prevention of neural synchronization: Multiple subpial transections (MST), to stop the spread and generation of a seizure intracortically.
selected cases but can be performed in older co-operative children and adolescents. Ictal SPECT and interictal PET may be used as adjunctive tests to add further information. Magnetoencephalography (MEG) can complement the scalp EEG data in defining the extent and location of the epileptogenic zone. In children, a noninvasive approach is preferred, more recently made possible by developments in neuroimaging.
Role of imaging in presurgical evaluation of epilepsy
The goals of neuroimaging in patients with medically refractory epilepsy are 1. delineation of structural and functional abnormalities in the suspected epileptogenic region, 2. prediction of the nature of structural pathology, 3. detection of abnormalities distant from the epileptogenic region (dual pathology), and 4. identification of the eloquent brain regions such as language, memory, and sensorimotor areas and the relation of these regions to the epileptogenic
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region.[16] The images should be reviewed by radiologists specially interested and experienced in the evaluation of patients with epilepsy.
Structural neuroimaging: MRI brain
Positive pathology is a favorable predictor of outcome after surgery, and MRI has enabled the detection of pathology preoperatively. [17] The common abnormalities identified by MRI in children with refractory epilepsy are mesial temporal atrophy and sclerosis (MTS), malformations of cortical development, primary brain tumors, vascular malformations, and focal atrophic lesions [Figures 1a-g]. The structural MRI protocol for patients with chronic epilepsy is summarized in Table 4.[18] In MTS, the hippocampus is best visualized by acquiring thin slices (1-3 mm) orthogonal to its long axis. The important MRI features of MTS are 1. abnormal increased signal of hippocampus and amygdala relative to other gray matter on T2-weighted (T2W) images, 2. atrophic changes in the hippocampus/amygdala or temporal lobe in T1W images, 3. abnormal increased signal in gray/white matter of the temporal lobe relative to the gray matter elsewhere, 4. atrophy of the ipsilateral fornix, 5. dilatation of the temporal horn, and 6. blurring of gray and white-matter margin in the temporal neocortex. In addition, there may be lesions associated with ipsilateral MTS such as migrational disorders, porencephalic cysts, and neoplasms (dual pathology). MRI has about 90% sensitivity and specificity in detecting MTS and other abnormalities in the rest of the temporal lobe. Detection of temporal lobe abnormalities may be enhanced by using quantitative and semiquantitative techniques such as T2 relaxometry, hippocampal volumetry, and proton magnetic resonance spectroscopy. Such techniques are mostly available only in centers specializing in epilepsy surgery, and therefore a normal routine MRI in the presence of clinical or EEG suspicion of focal epilepsy or both does not preclude referral. Malformations of cortical development are being increasingly recognized in patients with refractory epilepsy. They may be focal cortical dysplasia (FCD), lissencephaly, heterotopia, polymicrogyria, and schizencephaly.[19] Patients with lowgrade primary brain tumors frequently present with seizures. The underlying histopathologies include dysembryoplastic neuroepithelial tumor, ganglioglioma, gangliocytoma, and pilocytic and fibrillary astrocytoma. These lesions have low signal on T1 and high signal on T2W images. Cyst formation and enhancement with gadolinium may occur. Calcification is present in some cases. Cavernous angiomas are circumscribed and have the characteristic appearance of a range of blood products on MRI. Newly developed MRI techniques, diffusion weighted imaging (DWI), diffusion tensor imaging (DTI), and tractography improve the sensitivity of MRI. In children undergoing evaluation for hemispherotomy, MRI plays a major role, not only in giving information regarding the extent and nature of the hemispheric abnormality but also in excluding the presence of any abnormality on the contralateral side, which may be a predictor of an unfavorable outcome. One should carefully look for a hypothalamic hamartoma (HH) in children with normal MRI brain and refractory epilepsy especially with gelastic seizures.
a
b
c
d
e
f
g
Figure 1: Common imaging abnormalities in children with refractory epilepsy. (a) Focal cortical dysplasia ( T2 weighted images showing right frontal Taylor's type focal cortical dysplasia.) (b) Left mesial temporal sclerosis (FLAIR image showing hyperintesity of the hippocampus) in a 14 year child with refractory TLE. (c). Right hippocampal calcification. (d) Right temporal cavernoma.(e) Right perisylvian dysembryoblastic neuroepthelail tumor (DNET). (f) Right parietal gliosis in a 9 year child with refractory epilepsy. (g) Right temporal low grade glioma. FLAIR = Fluid attenuated inversion recovery
Table 4: MRI protocol for patients with chronic epilepsy[18] T1W images in axial and sagittal planes, and T2W and proton density sequences in axial and coronal planes, with 5 mm thickness and zero spacing, and T1W 3D SPGR images in coronal plane with 1.5 mm slice thickness. FLAIR sequences, if indicated. Gadolinium enhancement, if indicated. Quantitative MRI 3D image acquisition Hippocampal volumetry FLAIR = Fluid attenuated inversion recovery, MRI = Magnetic resonance imaging, SPGR = Spoiled gradient echo, 3D = Three dimensional, T1W = T1-weighted
Functional imaging: Role of SPECT and PET
Ictal SPECT and interictal fluorodeoxyglucose (FDG)-PET remain important imaging tools in the presurgical evaluation of children with refractory partial epilepsy. The two commonly used tracers for SPECT are 99-TC-hexamethylene propylaxamine (99Tc-HMPAO) and 99m Tc ethyl cysteinate dimer (99m Tc-ECD). SPECT measures blood flow and by comparing interictal and ictal SPECT studies, the increase in blood flow of certain brain regions during the ictal phase with respect to the interictal period can be evaluated. During ictal SPECT, due to epileptic activation, the neurons located in these areas are hyperactive, and there is an increase in blood flow as an autoregulatory response. The limitations of ictal SPECT are the following: 1. The dye reaches the brain at least 1 minute after the seizure onset, a time at which significant seizure spread has already occurred. 2. The spatial resolution of the images is low. An ictal SPECT displays both the ictal-onset zone and seizure propagation pathways. In common practice, the region with the largest and most intense hyperperfusion is considered as the
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ictal-onset zone [Figures 2a and b]. An ictal injection delay of less than 20 seconds after seizure onset significantly correlates with correct localization.[20] FDG-PET is more useful for lateralizing than localizing the epileptic focus.[18] Patients with MTS have low glucose metabolism in the whole temporal lobe [Figure 3], whereas patients with mesiobasal temporal tumors show only a slight decrease in metabolism. There is no correlation found between the degree of hypometabolism and the location of the epileptic focus. Unilateral focal temporal hypometabolism in 18FDG-PET predicts a good outcome after surgery for temporal lobe epilepsy (TLE).[19] The diagnostic sensitivity of FDG-PET as analyzed by statistical parametric mapping (SPM) was 44% in patients with refractory partial epilepsy and normal MRI. Video EEG semiology and ictal onset may be misleading in infants and young children.[21, 22] In such cases, noninvasive functional imaging in the form of ictal SPECT or interictal PET may provide useful information. The value of ictal SPECT has been enhanced by the use of subtraction ictal SPECT coregistered with MRI (SISCOM).[23]
Neuropsychology
Neuropsychological assessment plays an important role in the determination of verbal and nonverbal function in older children and in the determination of cerebral dominance.[12] Wada (sodium amytal) testing may be required in older children to lateralize language function, particularly where there has been relatively late onset of the epilepsy. However, in the presence of early-onset localization-related epilepsy, particularly associated with a structural abnormality, relocalization of function (i.e., language) is likely. Functional imaging techniques (in the form of MRI or PET) are being increasingly used to localize language function, although they are likely to be reliable only in the older child who is able to understand the required task and is able to lie within the magnet unsedated.[24] Such investigative techniques may preclude the need for Wada testing.
a
Role of noninvasive EEG in presurgical evaluation
In TLE, adolescents and older children have semiology similar to adults. Infants and toddlers are more likely to display seizure semiologies reminiscent of extratemporal and generalized epilepsies. An inverse relationship between the occurrences of ictal motor manifestations and age was shown in previous studies.[25-29] Such motor manifestations include tonic, clonic, myoclonic, and hypermotor seizures and epileptic spasms and may be mistaken for extratemporal seizures. The occurrence of epileptic spasms in young children with temporal lobe pathology is likely secondary to rapid secondary generalization of focal-onset seizures via dysfunctional cortical–subcortical interactions (particularly involving the thalamus, basal ganglia, and other brainstem structures). This can result in the generalized semiologic and EEG appearances, making identification of the ictal-onset zone difficult. It is also difficult to assess for the presence of auras in the very young. Beyond the age of 6 years, most children with TLE display much of the same seizure semiology as their adult counterparts.
The interictal and ictal EEG
The interictal EEG in TLE is typically characterized by temporal spike or sharp-wave discharges and temporal intermittent rhythmic delta activity (TIRDA). Temporal spike or sharpwave discharges are highly epileptogenic discharges that are maximal over the anterior temporal region. There is often increased activation of spike and sharp-wave discharges during drowsiness and sleep, with nearly 90% of the patients with temporal lobe seizures showing spikes during sleep. The spikewave discharges may occur independently or synchronously over the bilateral temporal regions. However, most patients with bitemporal interictal EEG patterns are found to have unilateral temporal lobe seizures. However, the interictal EEG frequently shows generalized and multifocal EEG abnormalities. The scalp ictal and interictal EEG recordings in children may be poorly localizing, even in TLE, due to incomplete or abnormal brain maturation. A focal lesion can present with generalized or multifocal epileptiform discharges in infants and young children. Similarly, the ictal EEG in a focal seizure of anterior temporal lobe origin may initially demonstrate lateralized or generalized scalp EEG changes.[30] Typically, the scalp EEG during a temporal lobe seizure demonstrates moderate- to highamplitude rhythmic paroxysmal activity that is maximal over a unilateral temporal region. This may progress to generalized rhythmic slowing that is maximal on the side of seizure onset.
b
c Figure 2: Hyperperfusion on ictal SPECT (a) and hypoperfusion on interictal SPECT (b) in a child with TLE. (c) Posterior parietal ictal hyperperfusion in a child with refractory extratemporal epilepsy. SPECT = Single-photon emission computerized tomography; TLE = Temporal lobe epilepsy
Figure 3: Interictal FDG-PET (axial and coronal images) showing left temporal hypometabolism in a 12-year-old child with TLE and left HS. FDG-PET = Fluorodeoxyglucose positron emission tomography; HS = Hippocampal sclerosis; TLE = Temporal lobe epilepsy
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Invasive monitoring
Intracranial EEG recording is indicated for precise localization of the epileptogenic zone, when located close to the functional cortex for planning a safe resection. Stereotactically inserted depth electrode area indicates when EEG recording is needed from buried gray matter that is not accessible with other electrodes. According to Mayo clinic experience, invasive recordings in TLE were deemed necessary for (a) inability to accurately localize the site of seizure onset by surface EEG, (b) suspected multifocal onset, and (c) discrepancies between MRI findings and video EEG monitoring [Figure 4a]. [31] Stereotactic depth recordings, when combined with scalp EEG recording, the so-called stereo EEG (SEEG), helps in clear delineation of the epileptogenic zone in complex cases. The complications of depth electrodes are intracerebral hemorrhage, in 1-4% cases, with rare fatalities and infection. The current use of subdural electrode grids by experienced centers has been shown to be well tolerated, even in young children, and allows not only accurate localization of seizure onset, but also localization of function.[32] This may be particularly necessary in children with extratemporal epilepsy, either in those with normal structural imaging (with highly concordant functional data) or with a structural abnormality thought to be close in proximity to the cortex involved in useful function [Figure 4b].
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Table 5: Selection criteria for childhood epilepsy surgery Resective surgery Seizures arise from a distinct area of the brain The epileptogenic area is functionally silent Drug-resistant epilepsy Hemispherotomy One-hemispherical structural abnormality Seizures lateralized to the abnormal hemisphere Pre-existing neurological deficit due to the underlying cause Drug-resistant epilepsy Hypothalamic hamartoma Children with drug-resistant epilepsy Progressive cognitive, developmental decline Corpus callosotomy Children with disabling drop attacks Drug-resistant epilepsy Severe mental retardation Vagal nerve stimulation Children with drug-resistant epilepsy who are not candidates for resective epilepsy surgery
Magnetoencephalography
Whole-head MEG facilitates simultaneous recording from the entire brain surface. Localizations of interictal spike zone with MEG showed excellent agreement with invasive EEG recordings. MEG is useful for the study of patients with nonlesional neocortical epilepsy and in patients with large lesions; it provides unique information on the epileptogenic zone. MEG can be used to map the sensorimotor cortex and language cortex. Both EEG and MEG yield complementary and confirmatory information.[33] Successful epilepsy surgery requires a multidisciplinary team approach with discussion of individual patient presurgical evaluation data in detail in a patient management conference. It will improve patient care and communication among members of the team. None of the currently available preoperative workups can exactly delineate the epileptogenic zone. However, with the multimodality presurgical evaluation approach, sufficient concordance could be established among various independent investigation, thus identifying location and extent of the epileptogenic zone with a high degree of confidence. This will result in a good surgical outcome. Surgically remediable epilepsy syndromes of childhood Surgery can be considered at any age in the pediatric population from infancy through early childhood and adolescence. The surgically remediable epilepsies in children are TLE with hippocampal sclerosis (HS), lesional temporal and extratemporal epilepsy, hemispherical epilepsy syndrome, and HH. Table 5 summarizes the criteria for selection of children with refractory epilepsy and the various surgical procedures. Temporal lobe epilepsy Surgery for TLE is the commonest surgery performed in adults, and most of them have their seizure onset in childhood or
a
b
Figure 4: Invasive EEG: Temporal depth electrodes (a) in a child patient with refractory TLE and discordant presurgical data and subdural grid (b) in a child. EEG = Electroencephalography
adolescence. Many children with TLE continue to have seizures in spite of adequate AED therapy. Children with medically refractory TLE should be evaluated appropriately for surgical management. Hippocampal sclerosis and dual pathology (hippocampal sclerosis and other lesion) were associated with only 11% and 3% seizure freedom at last follow-up in medically treated cases, respectively.[34] Early surgical intervention avoids the long-term risks associated with AED therapy. Children undergoing temporal lobectomy for refractory epilepsy show improvement in quality of life, visual memory, and attentional functions after surgery.[34] The complication rates are less than 5%.[7,35]
Presurgical evaluation
Ictal scalp EEG monitoring is essential for determining the region of seizure onset, especially for differentiating mesial versus neocortical onset. Patients with mesial TLE may have higher seizure-free outcomes with surgery compared to patients with neocortical temporal and extratemporal lobe epilepsies, particularly if a single MRI lesion is present.[36] MRI-positive TLE is associated with a favorable outcome. Patients with lesional TLE, such as hippocampal sclerosis or foreign tissue
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lesions (tumor, vascular anomaly), have a higher probability of seizure freedom after resection than those with normal MRI.[37] Postsurgical seizure-free outcome is seen in 70% to 90% patients with mesial TLE with hippocampal sclerosis compared to lowered seizure-free outcome of 60% in patients with nonlesional TLE.[36] Multimodality noninvasive imaging modalities are increasingly used to determine the presumed epileptogenic focus when the scalp EEG and MRI are nonlocalizing or normal. These include ictal SPECT, SISCOM, PET, MEG, and MR spectroscopy. The ability of SISCOM to detect epileptogenic lesions is 88% as compared to 39% by ictal SPECT alone. In patients with TLE and normal MRI, unilateral PET hypometabolism has a positive predictive value between 70% and 80%.[38] Neuropsychological assessment prior to pediatric epilepsy surgery includes age-appropriate, standardized tests to evaluate multiple domains: intelligence, language, memory, attention, problem solving/executive function, visuospatial and perceptual analysis and reasoning, academic skills, motor and sensory function, behavior, personality, emotional status, and adaptive functioning. It identifies areas of existing dysfunction, assists in determining language lateralization, and provides guidance in weighing the risks and benefits of surgery. It has been shown that verbal memory dysfunction was worst among children with left temporal lesions compared to those with right-sided lesions and controls, whereas nonverbal dysfunction was most prominent among children with right TLE. Children with TLE were found to have a long-lasting impact on verbal learning and memory. When compared to controls, children and adolescents with epilepsy failed to build up an adequate learning and memory performance.[39] Intracarotid sodium amobarbital testing (Wada test) is used to determine language lateralization and to screen for verbal memory dominance. Among children who underwent temporal lobectomy, better verbal memory performance after injection ipsilateral to the side of surgery than after contralateral injection (Wada memory asymmetries) predicted preserved postoperative verbal memory capacity.[40] The difficulty is co-operation of the child. Those at greater risk of poor co-operation include children with full-scale intelligence quotient (IQ)
Key Words Children, epilepsy surgery, temporal lobe epilepsy, extratemporal epilepsy, hemispherotomy For correspondence: Dr. Sita Jayalakshmi, Department of Neurology, Krishna Institute of Medical Sciences,
1-8-31/1, Minister Road, Secunderabad, Andhra Pradesh, India. E-mail: [email protected] Ann Indian Acad Neurol 2014:17 (Supplement 1):S69-79
Introduction Approximately 60% of all patients with epilepsy suffer from focal epilepsy syndromes. In about 15% of these patients, the seizures are not adequately controlled with anticonvulsive drugs, and such patients are potential candidates for surgical treatment. Around 65% of newly diagnosed epilepsy patients have a good response to antiepileptic drugs (AEDs). However, about 35% of patients have incompletely controlled epilepsy.[1] A major proportion of epileptic patients falls in the pediatric group (18 years or less), and approximately 25% of them have medically intractable epilepsy. Advances in neuroimaging and neurosurgical techniques have helped in selecting an increasing number of children with refractory epilepsies into the pediatric epilepsy surgery programs. Surgery has become an accepted treatment modality for carefully selected adults with intractable focal epilepsy. Epilepsy surgery in children who have been carefully chosen Access this article online Quick Response Code:
Website: www.annalsofian.org
DOI: 10.4103/0972-2327.128665
can result in either seizure freedom or a marked (>90%) reduction in seizures in approximately two-thirds of the children with intractable seizures.[2,3] Infants and children benefit from epilepsy surgery, with encouraging results published in recent series.[4-8] Consequences of ongoing seizures in childhood Poor developmental outcome in children is associated with earlier seizure onset.[9] Ongoing seizures in severe epilepsy has been shown to be associated with developmental delay and cognitive decline, and improvement in developmental outcome may be noted with early cessation of seizures.[10] Chronic AED therapy may be associated with adverse effects. Recurrent seizures are associated with behavioral and psychiatric problems, psychosocial consequences, poor quality of life of the child and family, and increased risk of injury and sudden death.[11] Unique features of pediatric epilepsy surgery Children are not small adults. Epilepsy surgery in children requires a careful approach during presurgical evaluation and surgical approach, as it is different from adults.[4,12] 1. Seizure frequency is high in children when compared to adults. 2. Frequent seizures in infants and children is associated with developmental arrest or regression, especially in children younger than 2 years. 3. Focal epilepsy in childhood is often associated with age-specific etiologies. Dysplasia is the commonest substrate in children, whereas hippocampal sclerosis is common in adults. 4. The presentation of intractable
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localization-related epilepsy is often heterogeneous in childhood. Pediatric patients with hemispheric or unilateral focal etiologies can have generalized seizures, generalized and multifocal electroencephalography (EEG) patterns, and rapid evolution of electroclinical features. 5. The child’s brain is capable of significant reorganization of neurologic function after insult and surgery, a unique and complex phenomenon that is critical for surgical planning. For example, interhemispheric language transfer occurs in children operated below the age of 6 years. Selection of the ideal candidate Epilepsy surgery is considered in children when 1. epilepsy is refractory, which is defined as inadequate control of seizures despite proper drug therapy with AED or the adequate control of epileptic seizures but with unacceptable side effects.[12] In adults, medical intractability may be considered as failure to respond to at least two anticonvulsant drugs over at least 2 years. These rules may not be appropriate in children and infants with catastrophic-onset epilepsies as seizure frequency may be such that a greater number of drugs are tried over a shorter time. In such cases, there is a need for early surgery for seizure freedom and prevention of developmental delay. 2. To be suitable for temporal or extratemporal epilepsy surgery, it should be proven that the seizures arise exclusively from one area of the brain that is functionally silent. Such an area of the brain may be relatively small or large, dependent partly on the underlying pathology and partly on the area of brain involved. The goals of epilepsy surgery should be clear [Table 1], and one should also understand when not to consider epilepsy surgery [Table 2]. Types of epilepsy surgery Currently, four types of surgical procedures are in practice[13] [Table 3]. They include the following: 1. Resection of the epileptogenic region responsible for the patient’s habitual seizures. 2. Interruption of pathways propagating seizures. 3. Decreasing brain excitability by stimulating structures exerting a restraining influence. 4. Prevention of neuronal synchronization. Presurgical evaluation The goals of presurgical evaluation are 1. To establish the diagnosis of epileptic seizure. 2. Define the electroclinical syndrome. 3. Delineate the lesion(s) responsible for the seizures. 4. Evaluate the past AED treatments and ensure that an adequate medical treatment had been provided. 5. Select ideal surgical candidates with optimal electro-clinicoradiologic correlation. 6. Ensure that the surgery will not result in disabling neuropsychological deficits.[14] Different diagnostic tools area being used by epileptologists to identify different cortical zones — symptomatogenic zone, irritative and ictal-onset zones, epileptogenic zone, and functional deficit zone, each one of which is more or less a precise index of the epileptogenic zone.[15] The current diagnostic techniques used in the definition of these cortical zones are video EEG monitoring, magnetic resonance imaging (MRI), ictal single-photon emission computerized tomography (SPECT), and positron emission tomography (PET). A detailed developmental, neuropsychological assessment and evaluation for behavioral problems should be performed. Intracarotid amobarbital (WADA) test and functional MRI (fMRI) are indicated in
Table 1: Goals of epilepsy surgery Removal of the lesional brain tissue — epileptogenic zone. Rendering the patient free of disabling seizures. Prevention of progressive side effects of epilepsy — physical, cognitive, psychosocial. Improvement in quality of life of the child, family.
Table 2: When not to consider epilepsy surgery Multiple epileptogenic foci. Single or predominant epileptogenic zone in nonresectable area (e.g., eloquent area). Progressive and/or diffuse neurological disorder or general medical contraindication. Severe/chronic psychiatric disorder.
Table 3: Surgical techniques Resective surgery: Removal of epileptogenic region responsible for patient’s habitual seizures Anterior temporal lobectomy with amygdalohippocampectomy Selective amygdalohippocampectomy Lesionectomy Cortical dysplasia Tumors (low-grade gliomas, dysembryoplastic neuroepithelial tumors) Gliosis ( secondary to old stroke or traumatic brain injury) Cavernoma Focal cerebral calcification Hemispherectomy/hemispherotomy Disconnection surgery: Interruption of pathways propagating discharges Corpus callosotomy — to stop the interhemispheric spread and synchronization of a seizure Disconnective technique — for hypothalamic hamartoma Stereotactic ablation Brain stimulation: Vagal nerve stimulation Deep brain stimulation Prevention of neural synchronization: Multiple subpial transections (MST), to stop the spread and generation of a seizure intracortically.
selected cases but can be performed in older co-operative children and adolescents. Ictal SPECT and interictal PET may be used as adjunctive tests to add further information. Magnetoencephalography (MEG) can complement the scalp EEG data in defining the extent and location of the epileptogenic zone. In children, a noninvasive approach is preferred, more recently made possible by developments in neuroimaging.
Role of imaging in presurgical evaluation of epilepsy
The goals of neuroimaging in patients with medically refractory epilepsy are 1. delineation of structural and functional abnormalities in the suspected epileptogenic region, 2. prediction of the nature of structural pathology, 3. detection of abnormalities distant from the epileptogenic region (dual pathology), and 4. identification of the eloquent brain regions such as language, memory, and sensorimotor areas and the relation of these regions to the epileptogenic
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region.[16] The images should be reviewed by radiologists specially interested and experienced in the evaluation of patients with epilepsy.
Structural neuroimaging: MRI brain
Positive pathology is a favorable predictor of outcome after surgery, and MRI has enabled the detection of pathology preoperatively. [17] The common abnormalities identified by MRI in children with refractory epilepsy are mesial temporal atrophy and sclerosis (MTS), malformations of cortical development, primary brain tumors, vascular malformations, and focal atrophic lesions [Figures 1a-g]. The structural MRI protocol for patients with chronic epilepsy is summarized in Table 4.[18] In MTS, the hippocampus is best visualized by acquiring thin slices (1-3 mm) orthogonal to its long axis. The important MRI features of MTS are 1. abnormal increased signal of hippocampus and amygdala relative to other gray matter on T2-weighted (T2W) images, 2. atrophic changes in the hippocampus/amygdala or temporal lobe in T1W images, 3. abnormal increased signal in gray/white matter of the temporal lobe relative to the gray matter elsewhere, 4. atrophy of the ipsilateral fornix, 5. dilatation of the temporal horn, and 6. blurring of gray and white-matter margin in the temporal neocortex. In addition, there may be lesions associated with ipsilateral MTS such as migrational disorders, porencephalic cysts, and neoplasms (dual pathology). MRI has about 90% sensitivity and specificity in detecting MTS and other abnormalities in the rest of the temporal lobe. Detection of temporal lobe abnormalities may be enhanced by using quantitative and semiquantitative techniques such as T2 relaxometry, hippocampal volumetry, and proton magnetic resonance spectroscopy. Such techniques are mostly available only in centers specializing in epilepsy surgery, and therefore a normal routine MRI in the presence of clinical or EEG suspicion of focal epilepsy or both does not preclude referral. Malformations of cortical development are being increasingly recognized in patients with refractory epilepsy. They may be focal cortical dysplasia (FCD), lissencephaly, heterotopia, polymicrogyria, and schizencephaly.[19] Patients with lowgrade primary brain tumors frequently present with seizures. The underlying histopathologies include dysembryoplastic neuroepithelial tumor, ganglioglioma, gangliocytoma, and pilocytic and fibrillary astrocytoma. These lesions have low signal on T1 and high signal on T2W images. Cyst formation and enhancement with gadolinium may occur. Calcification is present in some cases. Cavernous angiomas are circumscribed and have the characteristic appearance of a range of blood products on MRI. Newly developed MRI techniques, diffusion weighted imaging (DWI), diffusion tensor imaging (DTI), and tractography improve the sensitivity of MRI. In children undergoing evaluation for hemispherotomy, MRI plays a major role, not only in giving information regarding the extent and nature of the hemispheric abnormality but also in excluding the presence of any abnormality on the contralateral side, which may be a predictor of an unfavorable outcome. One should carefully look for a hypothalamic hamartoma (HH) in children with normal MRI brain and refractory epilepsy especially with gelastic seizures.
a
b
c
d
e
f
g
Figure 1: Common imaging abnormalities in children with refractory epilepsy. (a) Focal cortical dysplasia ( T2 weighted images showing right frontal Taylor's type focal cortical dysplasia.) (b) Left mesial temporal sclerosis (FLAIR image showing hyperintesity of the hippocampus) in a 14 year child with refractory TLE. (c). Right hippocampal calcification. (d) Right temporal cavernoma.(e) Right perisylvian dysembryoblastic neuroepthelail tumor (DNET). (f) Right parietal gliosis in a 9 year child with refractory epilepsy. (g) Right temporal low grade glioma. FLAIR = Fluid attenuated inversion recovery
Table 4: MRI protocol for patients with chronic epilepsy[18] T1W images in axial and sagittal planes, and T2W and proton density sequences in axial and coronal planes, with 5 mm thickness and zero spacing, and T1W 3D SPGR images in coronal plane with 1.5 mm slice thickness. FLAIR sequences, if indicated. Gadolinium enhancement, if indicated. Quantitative MRI 3D image acquisition Hippocampal volumetry FLAIR = Fluid attenuated inversion recovery, MRI = Magnetic resonance imaging, SPGR = Spoiled gradient echo, 3D = Three dimensional, T1W = T1-weighted
Functional imaging: Role of SPECT and PET
Ictal SPECT and interictal fluorodeoxyglucose (FDG)-PET remain important imaging tools in the presurgical evaluation of children with refractory partial epilepsy. The two commonly used tracers for SPECT are 99-TC-hexamethylene propylaxamine (99Tc-HMPAO) and 99m Tc ethyl cysteinate dimer (99m Tc-ECD). SPECT measures blood flow and by comparing interictal and ictal SPECT studies, the increase in blood flow of certain brain regions during the ictal phase with respect to the interictal period can be evaluated. During ictal SPECT, due to epileptic activation, the neurons located in these areas are hyperactive, and there is an increase in blood flow as an autoregulatory response. The limitations of ictal SPECT are the following: 1. The dye reaches the brain at least 1 minute after the seizure onset, a time at which significant seizure spread has already occurred. 2. The spatial resolution of the images is low. An ictal SPECT displays both the ictal-onset zone and seizure propagation pathways. In common practice, the region with the largest and most intense hyperperfusion is considered as the
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ictal-onset zone [Figures 2a and b]. An ictal injection delay of less than 20 seconds after seizure onset significantly correlates with correct localization.[20] FDG-PET is more useful for lateralizing than localizing the epileptic focus.[18] Patients with MTS have low glucose metabolism in the whole temporal lobe [Figure 3], whereas patients with mesiobasal temporal tumors show only a slight decrease in metabolism. There is no correlation found between the degree of hypometabolism and the location of the epileptic focus. Unilateral focal temporal hypometabolism in 18FDG-PET predicts a good outcome after surgery for temporal lobe epilepsy (TLE).[19] The diagnostic sensitivity of FDG-PET as analyzed by statistical parametric mapping (SPM) was 44% in patients with refractory partial epilepsy and normal MRI. Video EEG semiology and ictal onset may be misleading in infants and young children.[21, 22] In such cases, noninvasive functional imaging in the form of ictal SPECT or interictal PET may provide useful information. The value of ictal SPECT has been enhanced by the use of subtraction ictal SPECT coregistered with MRI (SISCOM).[23]
Neuropsychology
Neuropsychological assessment plays an important role in the determination of verbal and nonverbal function in older children and in the determination of cerebral dominance.[12] Wada (sodium amytal) testing may be required in older children to lateralize language function, particularly where there has been relatively late onset of the epilepsy. However, in the presence of early-onset localization-related epilepsy, particularly associated with a structural abnormality, relocalization of function (i.e., language) is likely. Functional imaging techniques (in the form of MRI or PET) are being increasingly used to localize language function, although they are likely to be reliable only in the older child who is able to understand the required task and is able to lie within the magnet unsedated.[24] Such investigative techniques may preclude the need for Wada testing.
a
Role of noninvasive EEG in presurgical evaluation
In TLE, adolescents and older children have semiology similar to adults. Infants and toddlers are more likely to display seizure semiologies reminiscent of extratemporal and generalized epilepsies. An inverse relationship between the occurrences of ictal motor manifestations and age was shown in previous studies.[25-29] Such motor manifestations include tonic, clonic, myoclonic, and hypermotor seizures and epileptic spasms and may be mistaken for extratemporal seizures. The occurrence of epileptic spasms in young children with temporal lobe pathology is likely secondary to rapid secondary generalization of focal-onset seizures via dysfunctional cortical–subcortical interactions (particularly involving the thalamus, basal ganglia, and other brainstem structures). This can result in the generalized semiologic and EEG appearances, making identification of the ictal-onset zone difficult. It is also difficult to assess for the presence of auras in the very young. Beyond the age of 6 years, most children with TLE display much of the same seizure semiology as their adult counterparts.
The interictal and ictal EEG
The interictal EEG in TLE is typically characterized by temporal spike or sharp-wave discharges and temporal intermittent rhythmic delta activity (TIRDA). Temporal spike or sharpwave discharges are highly epileptogenic discharges that are maximal over the anterior temporal region. There is often increased activation of spike and sharp-wave discharges during drowsiness and sleep, with nearly 90% of the patients with temporal lobe seizures showing spikes during sleep. The spikewave discharges may occur independently or synchronously over the bilateral temporal regions. However, most patients with bitemporal interictal EEG patterns are found to have unilateral temporal lobe seizures. However, the interictal EEG frequently shows generalized and multifocal EEG abnormalities. The scalp ictal and interictal EEG recordings in children may be poorly localizing, even in TLE, due to incomplete or abnormal brain maturation. A focal lesion can present with generalized or multifocal epileptiform discharges in infants and young children. Similarly, the ictal EEG in a focal seizure of anterior temporal lobe origin may initially demonstrate lateralized or generalized scalp EEG changes.[30] Typically, the scalp EEG during a temporal lobe seizure demonstrates moderate- to highamplitude rhythmic paroxysmal activity that is maximal over a unilateral temporal region. This may progress to generalized rhythmic slowing that is maximal on the side of seizure onset.
b
c Figure 2: Hyperperfusion on ictal SPECT (a) and hypoperfusion on interictal SPECT (b) in a child with TLE. (c) Posterior parietal ictal hyperperfusion in a child with refractory extratemporal epilepsy. SPECT = Single-photon emission computerized tomography; TLE = Temporal lobe epilepsy
Figure 3: Interictal FDG-PET (axial and coronal images) showing left temporal hypometabolism in a 12-year-old child with TLE and left HS. FDG-PET = Fluorodeoxyglucose positron emission tomography; HS = Hippocampal sclerosis; TLE = Temporal lobe epilepsy
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Invasive monitoring
Intracranial EEG recording is indicated for precise localization of the epileptogenic zone, when located close to the functional cortex for planning a safe resection. Stereotactically inserted depth electrode area indicates when EEG recording is needed from buried gray matter that is not accessible with other electrodes. According to Mayo clinic experience, invasive recordings in TLE were deemed necessary for (a) inability to accurately localize the site of seizure onset by surface EEG, (b) suspected multifocal onset, and (c) discrepancies between MRI findings and video EEG monitoring [Figure 4a]. [31] Stereotactic depth recordings, when combined with scalp EEG recording, the so-called stereo EEG (SEEG), helps in clear delineation of the epileptogenic zone in complex cases. The complications of depth electrodes are intracerebral hemorrhage, in 1-4% cases, with rare fatalities and infection. The current use of subdural electrode grids by experienced centers has been shown to be well tolerated, even in young children, and allows not only accurate localization of seizure onset, but also localization of function.[32] This may be particularly necessary in children with extratemporal epilepsy, either in those with normal structural imaging (with highly concordant functional data) or with a structural abnormality thought to be close in proximity to the cortex involved in useful function [Figure 4b].
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Table 5: Selection criteria for childhood epilepsy surgery Resective surgery Seizures arise from a distinct area of the brain The epileptogenic area is functionally silent Drug-resistant epilepsy Hemispherotomy One-hemispherical structural abnormality Seizures lateralized to the abnormal hemisphere Pre-existing neurological deficit due to the underlying cause Drug-resistant epilepsy Hypothalamic hamartoma Children with drug-resistant epilepsy Progressive cognitive, developmental decline Corpus callosotomy Children with disabling drop attacks Drug-resistant epilepsy Severe mental retardation Vagal nerve stimulation Children with drug-resistant epilepsy who are not candidates for resective epilepsy surgery
Magnetoencephalography
Whole-head MEG facilitates simultaneous recording from the entire brain surface. Localizations of interictal spike zone with MEG showed excellent agreement with invasive EEG recordings. MEG is useful for the study of patients with nonlesional neocortical epilepsy and in patients with large lesions; it provides unique information on the epileptogenic zone. MEG can be used to map the sensorimotor cortex and language cortex. Both EEG and MEG yield complementary and confirmatory information.[33] Successful epilepsy surgery requires a multidisciplinary team approach with discussion of individual patient presurgical evaluation data in detail in a patient management conference. It will improve patient care and communication among members of the team. None of the currently available preoperative workups can exactly delineate the epileptogenic zone. However, with the multimodality presurgical evaluation approach, sufficient concordance could be established among various independent investigation, thus identifying location and extent of the epileptogenic zone with a high degree of confidence. This will result in a good surgical outcome. Surgically remediable epilepsy syndromes of childhood Surgery can be considered at any age in the pediatric population from infancy through early childhood and adolescence. The surgically remediable epilepsies in children are TLE with hippocampal sclerosis (HS), lesional temporal and extratemporal epilepsy, hemispherical epilepsy syndrome, and HH. Table 5 summarizes the criteria for selection of children with refractory epilepsy and the various surgical procedures. Temporal lobe epilepsy Surgery for TLE is the commonest surgery performed in adults, and most of them have their seizure onset in childhood or
a
b
Figure 4: Invasive EEG: Temporal depth electrodes (a) in a child patient with refractory TLE and discordant presurgical data and subdural grid (b) in a child. EEG = Electroencephalography
adolescence. Many children with TLE continue to have seizures in spite of adequate AED therapy. Children with medically refractory TLE should be evaluated appropriately for surgical management. Hippocampal sclerosis and dual pathology (hippocampal sclerosis and other lesion) were associated with only 11% and 3% seizure freedom at last follow-up in medically treated cases, respectively.[34] Early surgical intervention avoids the long-term risks associated with AED therapy. Children undergoing temporal lobectomy for refractory epilepsy show improvement in quality of life, visual memory, and attentional functions after surgery.[34] The complication rates are less than 5%.[7,35]
Presurgical evaluation
Ictal scalp EEG monitoring is essential for determining the region of seizure onset, especially for differentiating mesial versus neocortical onset. Patients with mesial TLE may have higher seizure-free outcomes with surgery compared to patients with neocortical temporal and extratemporal lobe epilepsies, particularly if a single MRI lesion is present.[36] MRI-positive TLE is associated with a favorable outcome. Patients with lesional TLE, such as hippocampal sclerosis or foreign tissue
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lesions (tumor, vascular anomaly), have a higher probability of seizure freedom after resection than those with normal MRI.[37] Postsurgical seizure-free outcome is seen in 70% to 90% patients with mesial TLE with hippocampal sclerosis compared to lowered seizure-free outcome of 60% in patients with nonlesional TLE.[36] Multimodality noninvasive imaging modalities are increasingly used to determine the presumed epileptogenic focus when the scalp EEG and MRI are nonlocalizing or normal. These include ictal SPECT, SISCOM, PET, MEG, and MR spectroscopy. The ability of SISCOM to detect epileptogenic lesions is 88% as compared to 39% by ictal SPECT alone. In patients with TLE and normal MRI, unilateral PET hypometabolism has a positive predictive value between 70% and 80%.[38] Neuropsychological assessment prior to pediatric epilepsy surgery includes age-appropriate, standardized tests to evaluate multiple domains: intelligence, language, memory, attention, problem solving/executive function, visuospatial and perceptual analysis and reasoning, academic skills, motor and sensory function, behavior, personality, emotional status, and adaptive functioning. It identifies areas of existing dysfunction, assists in determining language lateralization, and provides guidance in weighing the risks and benefits of surgery. It has been shown that verbal memory dysfunction was worst among children with left temporal lesions compared to those with right-sided lesions and controls, whereas nonverbal dysfunction was most prominent among children with right TLE. Children with TLE were found to have a long-lasting impact on verbal learning and memory. When compared to controls, children and adolescents with epilepsy failed to build up an adequate learning and memory performance.[39] Intracarotid sodium amobarbital testing (Wada test) is used to determine language lateralization and to screen for verbal memory dominance. Among children who underwent temporal lobectomy, better verbal memory performance after injection ipsilateral to the side of surgery than after contralateral injection (Wada memory asymmetries) predicted preserved postoperative verbal memory capacity.[40] The difficulty is co-operation of the child. Those at greater risk of poor co-operation include children with full-scale intelligence quotient (IQ)
